Neurokinin-1 Receptor Antagonists as a Potential Novel Therapeutic Option for Osteosarcoma Patients

Osteosarcoma is a bone tumor predominantly affecting children and adolescents with high malignant potential. It is a cause of serious public health challenges due to its high morbidity rates and metastatic potential. Metastasis in osteosarcoma may manifest either during treatment of the primary tumor, shortly after treatment, or a long time after the end of the treatment. So far, there are no therapeutics that can prevent or treat osteosarcoma metastasis. The peptide substance P (SP) and its high-affinity receptor, Neurokinin-1 (NK-1R), are known to positively correlate with osteosarcoma progression. Osteosarcoma cells overexpress NK-1R. SP is known to elicit the proliferation of osteosarcoma cells and induce angiogenesis and migration, leading to the invasion and metastasis of tumor cells. In contrast, NK-1R antagonists, such as aprepitant, inhibit the proliferation and induce the apoptosis of osteosarcoma cells. Aprepitant is also known to inhibit the migration of osteosarcoma cells, as well as reduce the expression levels and activities of transcriptional regulators of metastasis-related genes such as matrix metalloproteinases (MMP-2 and MMP-9), vascular endothelial growth factor (VEGF), and nuclear factor kappa B (NF-κB). These preceding studies highlighted the antimetastatic role of aprepitant in osteosarcoma Moreover, combination therapy consisting of chemotherapy and NK-1R antagonist increases the chemosensitization of osteosarcoma cells. Interestingly, this combination therapy in vitro and in vivo decreases the severe side-effects of chemotherapy and produces neuroprotection, hepatoprotection, nephroprotection, and cardioprotection. In this review, we provide an update on existing data and suggest the need to repurpose aprepitant for use as an antitumor drug for treatment of osteosarcoma, and they suggest the need for phase I and II clinical trials for assessment of its safety/efficacy.